The premise of this research is that: (1) both early life stress (ELS) and recent stressors increase risk for a wide range of mental disorders including major depressive disorder, but many people are resilient to both; and (2) micro RNAs (miRNAs) mediate shorter- and longer-term effects of environmental stressors on gene expression and cell function. The effects of both ELS and recent stressors involve the induction of shorter- and longer-term coordinated changes across networks of genes, mRNAs, and proteins. miRNAs are a subclass of non-coding RNAs that regulate gene expression via post-transcriptional mechanisms. miRNAs are responsive to environmental cues and function as transducers of environmental effects on gene expression. Further, single miRNAs can regulate a range of mRNA translation and tend to effect coordinated networks of genes. In addition, miRNAs are subject to epigenetic regulation. There is strong evidence that brain miRNAs are responsive to environmental stressors, and that they are adaptively regulated by early life stress. miRNAs directly and indirectly regulate components of both stress response (e.g., glucocorticoid receptor, corticotropin-releasing hormone receptor 1) and neuroplasticity (e.g., BDNF), and regulate stress- and fear-related neural mechanisms such as fear conditioning, extinction memory, and fear memory consolidation. However, there has been no research on the effects of either acute stress or ELS on miRNA expression in humans. Exosomes containing both miRNAs and mRNAs are released into the peripheral circulation. Using specific surface markers, we have successfully isolated neural-derived blood exosomes, which are enriched with miRNAs expressed in brain. The proposed study aims to examine the involvement of neural-specific exosomal miRNAs in both acute stress response and longer-term processes associated with ELS. Our primary outcome will compare people with either PTSD or major depression (MDD) with a history of ELS (that we will combine into an ELS-stress sensitive group [ELS-SS]) with a group of people with ELS but no history of mental disorder (ELS-SS). Participants will undergo an acute experimental stress, the Trier Social Stress Test (TSST); blood will be drawn at baseline and at times 0, 15, 30, 60, and 90 min following the test. miRNA sequencing will be conducted on the baseline and TSST+15 min samples and ELS-SS and ELS-SR groups will be compared. We anticipate that: (1) there will be significant differences between ELS-SS and ELS-SR groups in miRNA expression; (2) the TSST will alter the expression of set of neural-derived exosomal miRNAs that regulate components of neuroplasticity and stress response, which will be differentially expressed in ELS-SS and ELS- SR groups; (3) the alterations in miRNAs will be associated with differential methylation of miRNA sequences. This pilot and feasibility project has a high likelihood of leading to research that will change our understanding of how the environment modulates stress response, and why some people are sensitive to stress while others with similar stressors are resilient. This may lead to the development of novel treatments or prevention.